Topic  13      The Complement System

Introduction

The Complement system plays a critical role in the defense of the body in association with antibodies and cells of the immune system.  It is the major effector of the humoral branch of the immune system and consists of nearly 30 serum and membrane proteins.  Nature has devised two pathways for the activation of complement, the so-called classical pathway and the alternative pathway.  Although both pathways share some common components, they differ in the ways in which they are initiated.  The classical pathway requires antigen-antibody complexes for initiation, while the alternative pathway does not. 

This section describes the similarities and differences in the two pathways, the regulation of the complement system, the various effector functions of complement system, the effector functions of various complement components, and the consequences of hereditary deficiencies  in some components.

Objectives

On completion of this section and the required reading, you should be able to:

n  describe the nomenclature of complement components;

n  draw a concept map of the classical complement cascade;

n  draw a concept map of the alternate pathway of complement activation;

n  describe with specific examples the regulation of complement activation;

n  explain the ESSENTIAL differences between the classical and the alternative complement activation pathways;

n  discuss why the amplification phase is critical to many immune reactions;

n  specify the major sources of complement and comment on the regulation of the genetic control of complement proteins.

 

P Key Words

•           alternative pathway

•           anaphylatoxin inactivator

•           anaphylatoxins

•           C1

•           C1q

•           C1r

•           C1s

•           C1 inhibitor (C1-INH),

•           C2

•           C2a

•           C2b

•           C4

•           C4a 4b

•           C4 binding protein (C4-bp)

•           C5

•           C5a

•           C3

•           C3a

•           C3b

•           C3 convertase

•           C3b/C4b

•           receptor(CR1)

•           C5b

•           C5 convertase

•           C6

•           C7

•           C8

•           C9

•           CD59 classical pathway

•           amplification phase

•           activation phase

•           membrane attack phase

•           complement

•           complement system

•           Factor B

•           Factor D

P Key Concepts

n  Complement consists of a group of serum proteins that activate each other in an orderly fashion to generate biologically active molecules, such as enzymes, opsonins, anaphylatoxins, and chemotoxins.      

n  There are three separate enzyme pathways within the complement system: the classical pathway initiated by antibody bound to antigen; the alternative pathway initiated by foreign surface; and the terminal pathway that results in the destruction of microorganisms.

n  Activation of the complement system results in inflammation, chemotaxis, opsonization, and cell lysis.  It also regulates the immune system.

n  The level of complement does not increase after immunization.

n  The complement fixation test is based on the competition for complement between immune complexes consisting of anti-sheep red blood cell antibody and sheep red blood cells, in which the sheep erythrocytes lyse, and a second antigen-antibody system.  The greater the amount of the second system present, the more it will fix complement and inhibit the lysis of the sheep erythrocytes.

DID YOU KNOW?

In 1894 Pfeiffer discovered that cholera bacilli (Vibrio cholerae) were dissolved or lysed in vitro by the addition of guinea pig anti-choler serum.  Heating the serum at 56 C for 30 minutes abolished this activity, but did not abolish the activity of antibodies against the bacilli, since the heated serum could still transfer immunity passively from one guinea pig to another.  Pfeiffer discovered that the addition of normal, fresh serum to the heat-treated antiserum restored its lytic activity.  From these experiment, he concluded that antibodies to the bacilli, plus a heat-labile component present in immune as well as normal serum, were necessary for the lysis of V.cholerae in vitro. 

A few years later, Bordet confirmed that bacteriolysis by immune serum required a heat-labile component that he termed “Alexine."  The term complement, applied some years later by Elhrich, displaced “Alexine” and is used to denote the heat-labile components in normal serum which, together with antigen-bound antibodies, exhibit a variety of biological properties, one of which is the ability to lyse cells or microorganisms.  Complement consists of a group of serum proteins that act in concert and in orderly sequence to exert their effect.  These proteins are not immunoglobulins, and their concentrations in serum do not increase after immunization.  Like antibodies, they appear to have arisen late in evolution and are found only in vertebrates.

Bordet discovered that the action of complement, in the presence of the appropriate antiserum, results in the lysis of red blood cells.  Based on the observation, Bordet developed the complement fixation test.

As appeared in: Immunology a Short Course, 2nd edition.  E. Benjamini and S. Leskowitz.  Wiley-Liss, A John Wiley & Sons, INC., Publication, 1992

Review Questions

1. Textbook Study Questions

Review questions at the end of the Chapter 14.  The answers with explanations are available at the end of the textbook.

2.  Multiple Choice Questions

1.  Which class of immunoglobulin activates complement upon binding with antigen?

A) IgM

B)  IgA

C)  IgD

D) IgE

E)  all of the above

2.  Which complement component produces an anaphylatoxin?

A) C1

B)  C2

C)  C3

D) properdin

E)  immunoconglutinin

3.  Complement used for serological tests is usually derived from

A) horses

B)  guinea pigs

C)  sheep

D) cattle

E)  rabbits

 

 

4.  Which complement component has chemotactic  properties?

A) C1a

B)  c2a

C)  C4a

D) C5a

E)  C6a

5.  What is the major ligand for CR3?

A) C1

B)  C2

C)  C3b

D) C5

E)  C7

3. Definitions/Short Answer Questions

1.  Complement is involved in antigen-antibody interactions, yet there is no  agglutination or precipitation. What does happen?

2.  What are the important functions of complement?

3.  If complement activation can lead to lysis of antibody tagged cellular antigens, what is the purpose of complement activation by antibody-tagged non cellular antigens?

4.  Differentiate between the classical pathway and the alternate pathway of complement activation

5.  Briefly discuss the three stages of the classical pathway of complement activation. What stage is the most important? Why?

6.  What is the difference between complement activation by antigen-IgM complexes and antigen-IgG complexes?

7.  What is the biologic importance of C4a?

8.  What complement components make up C3 convertase and what does it do?

9.  Macrophages have receptors for C3b. What is the biologic significance of this fact?

10.   What is the last complement component to be split into two biologically active fragments? What are their functions?

11.   If the complement cascade is stopped before the membrane attack phase, has complement fulfilled its function in an immune response? If yes, why? If no speculate on the reason for having the membrane attack phase.

12.   What components of the complement system are shared between the classical pathway and the alternative pathway?

13.   Why is it important to tightly control complement activation?

Where to Go from Here

Once you have completed the review, take some time and complete the objectives. If you are having trouble with any of the concepts, contact your instructor.

When you are confident that you can complete the objectives, proceed to the next topic.